The goal of Project 4 is to determine if the susceptibility of pancreatic beta cells to undergo programmed cell death (apoptosis) plays a role in the development of insulin-dependent diabetes mellitus (IDDM). It has been established that IDDM is an autoimmune disease in which there is a selective loss of pancreatic beta cells. The progressive decline in the number of beta cells ultimately results in failure to produce insulin. Although both beta-cell -specific antibodies and beta-cell specific cellular immune responses develop during the course of the disease, the processes that trigger the beta-cell-specific autoimmune response are unknown. Current evidence suggests that the inflammatory lesion within the islet of Langerhans involves sequential recruitment of macrophages, CD4+ and CD8+ T cells, and B cells. While the recruitment of these cells are required to sustain an anti-beta cell immune response, it remains unclear what factors predispose to the initiation of the inflammatory response. Recently several genes known to regulate programmed cell death (apoptosis) have been linked to the pathogenesis of IDDM in the NOD mouse model. This suggests that genetic factors that predispose pancreatic beta cells to undergo programmed cell death may play a role in the initiation of an inflammatory response that ultimately leads to IDDM. Traditionally, it has been thought that apoptotic cell death is an immunologically silent event. For example cells die during organogenesis and tissue homeostasis without provoking an inflammatory response. In contrast, necrotic cell death following cell injury provides a proinflammatory signal tot he immune system. To date, there has been no systematic study of the factors that influence either the B cells's susceptibility to death or the subsequent immunological response to beta cell death. This project seeks to; 1) determine if the mechanism by which beta cells undergo cell death can have an effect on the magnitude of the subsequent immune response; 2) determine if genetically manipulated beta cells which have an increased propensity to resist cell death will alter the incidence or severity of diabetes in murine models of IDDM; 3) determine if pancreatic beta cells that have been genetically altered to enhance their resistance to programmed cell death will improve the success of islet cell transplantation in animals that have developed IDDM.